ZA200109624B - Salts of cis-c4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl) cyclohexan-1-carboxylate. - Google Patents
Salts of cis-c4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl) cyclohexan-1-carboxylate. Download PDFInfo
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- ZA200109624B ZA200109624B ZA200109624A ZA200109624A ZA200109624B ZA 200109624 B ZA200109624 B ZA 200109624B ZA 200109624 A ZA200109624 A ZA 200109624A ZA 200109624 A ZA200109624 A ZA 200109624A ZA 200109624 B ZA200109624 B ZA 200109624B
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- Prior art keywords
- cyclohexan
- cyclopentyloxy
- methoxyphenyl
- carboxylate
- cis
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- 150000003839 salts Chemical class 0.000 title claims description 16
- NZNMSOFKMUBTKW-UHFFFAOYSA-N cyclohexanecarboxylic acid Chemical compound OC(=O)C1CCCCC1 NZNMSOFKMUBTKW-UHFFFAOYSA-N 0.000 title 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 claims description 6
- 159000000000 sodium salts Chemical class 0.000 claims description 6
- 239000008194 pharmaceutical composition Substances 0.000 claims description 5
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical class OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 claims description 4
- -1 diamine salt Chemical class 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 35
- 239000000243 solution Substances 0.000 description 14
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 11
- 239000000203 mixture Substances 0.000 description 9
- 238000010992 reflux Methods 0.000 description 8
- 238000001953 recrystallisation Methods 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000011084 recovery Methods 0.000 description 5
- 238000003756 stirring Methods 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 238000000354 decomposition reaction Methods 0.000 description 4
- 235000019439 ethyl acetate Nutrition 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 238000001556 precipitation Methods 0.000 description 4
- 239000000725 suspension Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 102000004861 Phosphoric Diester Hydrolases Human genes 0.000 description 3
- 108090001050 Phosphoric Diester Hydrolases Proteins 0.000 description 3
- 239000007983 Tris buffer Substances 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 101100296719 Caenorhabditis elegans pde-4 gene Proteins 0.000 description 2
- 108010044467 Isoenzymes Proteins 0.000 description 2
- 229940123932 Phosphodiesterase 4 inhibitor Drugs 0.000 description 2
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 2
- 208000006673 asthma Diseases 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000012043 crude product Substances 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 210000000440 neutrophil Anatomy 0.000 description 2
- 239000012299 nitrogen atmosphere Substances 0.000 description 2
- 239000002587 phosphodiesterase IV inhibitor Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 102000003390 tumor necrosis factor Human genes 0.000 description 2
- 208000006545 Chronic Obstructive Pulmonary Disease Diseases 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical class NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 1
- 101000909851 Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv) cAMP/cGMP dual specificity phosphodiesterase Rv0805 Proteins 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 102000030621 adenylate cyclase Human genes 0.000 description 1
- 108060000200 adenylate cyclase Proteins 0.000 description 1
- 210000005091 airway smooth muscle Anatomy 0.000 description 1
- 210000005057 airway smooth muscle cell Anatomy 0.000 description 1
- 208000026935 allergic disease Diseases 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 239000000924 antiasthmatic agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 210000003651 basophil Anatomy 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- HJSLFCCWAKVHIW-UHFFFAOYSA-N cyclohexane-1,3-dione Chemical compound O=C1CCCC(=O)C1 HJSLFCCWAKVHIW-UHFFFAOYSA-N 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 210000003630 histaminocyte Anatomy 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 210000004969 inflammatory cell Anatomy 0.000 description 1
- 208000027866 inflammatory disease Diseases 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 210000001616 monocyte Anatomy 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 230000004648 relaxation of smooth muscle Effects 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- UDWXLZLRRVQONG-UHFFFAOYSA-M sodium hexanoate Chemical compound [Na+].CCCCCC([O-])=O UDWXLZLRRVQONG-UHFFFAOYSA-M 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C261/00—Derivatives of cyanic acid
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/45—Carboxylic acid nitriles having cyano groups bound to carbon atoms of rings other than six-membered aromatic rings
- C07C255/46—Carboxylic acid nitriles having cyano groups bound to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of non-condensed rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pulmonology (AREA)
- Immunology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
Salts of cis-[4-cyano-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexan-1-carboxylate]
The present invention relates to salts of a 4,4- disubstitutedphenylcyclohexanoic acid which are useful in treating allergic and inflammatory diseases and for inhibiting the production of Tumor Necrosis Factor (TNF).
Background of the Invention : It has been shown that a distinct cyclic nucleotide phosphodiesterase (PDE) isozyme, PDE 4, is responsible for cAMP breakdown in airway smooth muscle and inflammatory cells. {Torphy, "Phosphodiesterase Isozymes: Potential Targets for
Novel Anti-asthmatic Agents" in New Drugs for Asthma, Barnes, ed. IBC Technical
Services Lid., 1989]. Research indicates that inhibition of this enzyme not only produces airway smooth muscle relaxation, but also suppresses degranulation of mast cells, basophils and neutrophils along with inhibiting the activation of monocytes and neutrophils. Moreover, the beneficial effects of PDE 4 inhibitors are markedly potentiated when adenylate cyclase activity of target cells is elevated by appropriate hormones or autocoids, as would be the case in vivo. Thus PDE 4 inhibitors would be effective in the treatment of a number of diseases involving the pulmonary system.
One compound of interest in treating PDE 4-modulated diseases is cis-[4- cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan- 1 -carboxylate]. Itis described in U.S. patent 5,552,438. This compound has been effective in treating several forms of asthma, chronic obstructive pulmonary disease, and various other conditions modulated by drugs which inhibit PDE 4.
This invention covers certain salts of cis-[4-cyano-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexan-1-carboxylate] and the method for preparing these salts, namely the sodium salt, the ethylene diamine salt and the tristhydroxymethyl)aminomethane salt.
This invention also relates to the pharmaceutical compositions comprising these salts combined with a pharmaceutically acceptable carrief or diluegt.
Detailed Description of the iation ¥
The carboxylic acid, cis-[4-cyano-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexan-1-carboxylate] is prepared by the method described in us. patent 5,552,438 as well as by other route set forth in the likes of PCT application as WO98/34584 published 13 August 1998.
The salts of this invention and their preparation are described in the following examples.
Example 1A
Formation and Recrystallization of Sodium Salt 1(a) Formation of salt: A 50 ml 3 necked round bottom flask equipped with thermometer, reflux condenser, addition funnel and Nj; inlet was charged with 2.01 g (5.85 mmoles) of cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1- carboxylate] and 20ml of ethyl acetate at room temperature under a nitrogen atmosphere. The resulting mixture was warmed up to 55-60 °C over a period of 20 minutes and gave a clear colorless solution. To this solution was added a pre-made solution of 1.16 g (7.03 mmoles, 1.2 equivalents) of sodium hexanoate in 8.0 ml of ethyl acetate slowly over a 2 minute period while maintaining the reaction ~~ temperature between 50-60 °C. The contents of the flask were cooled to room ~~ temperature (18-20 °C) over a period of 30 minutes. Precipitation started at around 25-30 °C. The suspension was kept stirred at room temperature for one hour. The contents of flask were then filtered through a sintered funnel and the cake was rinsed with 2 x 10m of ethyl acetate. This crude product was dried under Hi-vac for 24 hours to give 1.64 g (76.5% yield) of the captioned sodium salt. M. P.: 238 °C. Karl
Fisher: 1.64%. 'H NMR was satisfactory. DSC indicated three small endotherms at 154.4 0C, 185.1 °C and 212.0 °C, one major endotherm at 230 °C and probable decomposition at 324.3 OC.
IR (KBr peliet): 3420, 2953, 2232, 1559, 1519, 1415, 1260, 1241, 1167, 1148, 1027, 992, 805 cm-l. 1(b) Recrystallization of Sodium Salt: A 25 ml 3 neck round bottom flask equipped with thermometer, reflux condenser, addition funnel and N; inlet was charged with 0.606 g (1.654 mmoles) of crude sodium salt product from Example
I(a) and 4.5 ml of acetonitrile at room temperature with stirring. To this thick suspension was added dionized water dropwise with heating up to 60 °C; a total of 0.3 ml water was added. The mixture changed to a clear pale yellow solution. The solution was air cooled to 45 °C, seeded with 2 mg of seed crystal and cooled further to 35 °C over 5 minutes. It was then placed in the freezer (-8 °C) for 16 hours. The contents of flask were then filtered through a sintered funnel and the filter cake was rinsed with 2 x 1.5 ml of acetonitrile. The product was dried under Hi-vac for 24 hours. Recovery from the recrystallization step was 0.568 g (93.56%). M. P. : >240 °C (turned to brown tar at 260 °C). DSC showed two small endotherms at 162.1 °C and 189.2 OC and one major endotherm at 232.7 OC, followed by probable decomposition at 333.0 OC. This profile was identical to the crude product; Karl
Fisher : 2.9%. This material, when exposed to air at room temperature for 1 week, had a 22.9% water content (Karl Fisher) indicating this salt is hydroscopic.
Recrystallization was also done using isopropyl alcohol with a 50% recovery and similar form of crystal (in terms of M. P., DSC, KF, IR and 'H NMR)
Example 2
Preparation of an Ethylene Diamine Salt 2(a) Formation of Salt: A 100 ml 3 neck round bottom flask equipped with a reflux condenser, thermometer, magnetic stirrer and Ny» inlet was charged with 6.15 g (16.51 mmoles) of cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan- 1-carboxylate] and 55 ml of isopropanol at room temperature under a N, atmosphere.
The resulting suspension was heated up to 60 °C with stirring, giving a clear light brown solution. To this mixture was added 0.60 ml (0.54 g, 8.96 mmoles, 0.51 equivalents ) of ethylene diamine in one portion. The resulting solution was kept at 60 °C for 15 minutes. The solution was then allowed to cool to 45 °C over 20 minutes and seeded with 2 mg of seed crystal. In a few seconds the salt started to precipitate. The cooling was continued to room temperature and then to 0 °C over 45 minutes. The suspension was stirred at 0 °C for an additional 2 hours after which it was filtered through a sintered glass funnel. The filter cake was rinsed with 2 x 2.0 ml of cold isopropyl alcohol. The product was dried under Hi-Vac for 20 hours. The isolated weight was 5.989 g (45.74% recovery, S0% in theory, 98.61% Wt/Wt assay). 'H NMR was satisfactory; M. P. : 158-161 °C; Karl Fisher : 0.15%; DSC one small endotherm at 77.4 °C , one major at 167.4 OC and probable decomposition at >180 OC; IR(KBr): 3379, 2959, 2860, 2638, 2229, 1617, 1519, 1414, 1268, 1234, 1148, 1024, 988, 936, 807, 739, 634 cm-l. 2(b) Recrystallization: A 25 ml 3 neck round bottom flask equipped with thermometer, reflux condenser, addition funnel and N; inlet was charged with 1.02 g of crude ethylene diamine salt (2.74 mmoles) prepared in 2(a) and 12.0 ml of isopropanol at room temperature (18-20 °C). The resulting mixture was heated to reflux at 90-92 °C over a period of 30 minutes, giving a clear brown solution.
Heating was stopped and the content of the reaction flask was air cooled to 63-65 °C over 30 minutes. The solution was seeded with pure ethylene diamine salt.
Crystallization started after a few minutes. The mixture was further cooled to room temperature and then further chilled to 0 °C in an ice water bath for 1.0 h. The solid was isolated by filtration and the filter cake was rinsed with 2 x 2.0 ml of isopropyl alcohol. The product was dried under Hi-vac at room temperature for 20 h.
Recovery was 90.1% (Wt=0.919 g). Karl Fisher : 0.075%; M. P. : 156-159 °C; 'H
NMR was satisfactory; DSC showed minor sharp endotherm at 81.46 °C and major sharp endotherm at 166.68 °C. IR(KBr) was identical to the crude product.
Recrystallization was also done in 99/1 isopropyl alcohol/H,0 (91.0%),
EtOAc /MeOH ( 74.8%) and gave a similar quality crystal.
Example 3
Tris(hydroxymethylaminomethane salt 3(a) Salt Formation: A SO ml three neck round bottom flask equipped with magnetic stirrer, reflux condenser, addition funnel, thermometer and N3 inlet was charged with 3.0 g (8.735 mmoles) of the acid and 30 ml of isopropanol at room temperature. The mixture was heated to 70 ©C with vigorous stirring to obtain a clear solution. While maintaining the reaction temperature at 70 ©C, there was added tris (hydroxymethyl)aminomethane (1.10 g, 9.091 mmoles, 1.04 equivalents) in a mixture of 8.0 ml of MeOH and 1.0 ml of deionized water (some heating was required to obtain a clear aqueous solution of amine). The resulting clear solution .. was stirred and cooled to room temperature for 2.0 hours without precipitation.
Upon stirring overnight (16 hours) at room temperature, a heavy precipitation formed. The slurry was diluted with 15 ml of isopropyl alcohol and transferred to a sintered funnel under house vacuum. The filter cake was rinsed with 2 x 5.0 ml of cold isopropyl alcohol (0-5 ©C). The filter cake was dried under Hi-vac for 72 hours yielding 2.713 g of white solid, i.e., crude tris salt of cis-[4-cyano-4-(3- cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylate] (66.9%). 1H NMR was satisfactory, M.P. : 143-147 OC; Karl Fisher : 1.73%; DSC had two sharp endotherm at 127.8 ©C, 140.9 OC and probable decomposition at 185 OC; IR(KBr pellet): 3513, 3327, 2954, 2865, 2233, 1590, 1519, 1409, 1197, 1258, 1244, 1197, 1168, 1147, 1122, 1095, 1063, 1048, 1028, 1002, 932, 806, 656, 635 cm-1. 3(b) Recrystallization: A 25 ml three neck round bottom flask was equipped with a magnetic stirrer, reflux condenser, addition funnel, thermometer and N3 inlet.
It was charged with 1.0 g of crude tris salt and 7 ml of isopropanol at room temperature under a nitrogen atmosphere. The resulting mixture was heated to reflux under nitrogen at 80-82 OC. After approximately 20 minutes, the mixture became a clear yellow solution. Heating was removed and the flask allowed to air cool. Upon reaching about 60 OC, rapid precipitation was observed. An additional 2.0 ml of isopropyl alcohol was added to facilitate a proper stirring. The solution was further cooled to room temperature over 45 minutes and then further chilled to 0-5 °C for 30 minutes in an ice water bath. The product was isolated by filtration through a sintered glass funnel and the cake was rinsed with 2 x 2 ml of cold isopropyl alcohol.
The wet solid was dried under Hi-vac for 24 hours yielding 0.888 g of recrystallized tris salt of cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1- carboxylate] (recovery was 88.8%). 1H NMR was satisfactory, M. P. :145-148 OC;
Karl Fisher: 0.32%; DSC indicated one sharp major endotherm at 147.1 ©C and one shoulder at 153.2 °C. IR (KBr) was identical to the crude product. 5 The recrystallization was also done in ethyl acetate/isopropy! alcohol (Y= 81.3%) and acetone isopropyl alcohol (Y = 50.50%).
Claims (8)
1. the sodium salt of cis-{4-cyano-4-(3-cyclopentyloxy-4- methoxyphenyl)cyclohexan-1-carboxylate].
2. The cthylene diamine salt of cis-[4-cyano4-(3-cyclopentyloxy—4- methoxyphenyl)cyclohexan-1-carboxylate].
3. The tris (hydroxymethyl)aminomethane salt of cis-{4-cyano-4-(3- cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylate].
4. A pharmaceutical formulation comprising sodium cis-[4-cyano-4-(3- cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylate] and a pharmaceutically acceptable excipient.
5. A pharmaceutical formulation comprising ethylene diamine cis-[4-cyano-4-(3- cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylate] and a pharmaceuticaily acceptable excipient.
6. A pharmaceutical formulation comprising tris (hydroxymethyl)aminomethane cis-[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan- 1-carboxylate] and a pharmaceutically acceptable excipient
7. The salt according to any one of claims 1 to 3, substantially as herein described and exemplified.
8. A pharmaceutical formulation according to any one of claims 4 to 6, substantially as herein described and exemplified. AMENDED SHEET
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US13573299P | 1999-05-25 | 1999-05-25 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ZA200109624B true ZA200109624B (en) | 2002-09-11 |
Family
ID=22469405
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ZA200109624A ZA200109624B (en) | 1999-05-25 | 2001-11-22 | Salts of cis-c4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl) cyclohexan-1-carboxylate. |
Country Status (20)
| Country | Link |
|---|---|
| EP (1) | EP1194142A4 (en) |
| JP (1) | JP2003500356A (en) |
| KR (1) | KR20020010669A (en) |
| CN (1) | CN1351491A (en) |
| AR (1) | AR024076A1 (en) |
| AU (1) | AU5304900A (en) |
| BR (1) | BR0010483A (en) |
| CA (1) | CA2375543A1 (en) |
| CO (1) | CO5170527A1 (en) |
| CZ (1) | CZ20014186A3 (en) |
| HK (1) | HK1046630A1 (en) |
| HU (1) | HUP0201265A3 (en) |
| IL (1) | IL146213A0 (en) |
| MX (1) | MXPA01012048A (en) |
| NO (1) | NO20015699D0 (en) |
| NZ (1) | NZ515169A (en) |
| PL (1) | PL351945A1 (en) |
| TR (1) | TR200103238T2 (en) |
| WO (1) | WO2000071114A1 (en) |
| ZA (1) | ZA200109624B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2003534238A (en) * | 1999-12-15 | 2003-11-18 | スミスクライン・ビーチャム・コーポレイション | Salt of cis-4-cyano-4- [3- (cyclopentyloxy) -4-methoxyphenyl] cyclohexane-1-carboxylic acid. |
| MX352804B (en) * | 2012-03-22 | 2017-12-08 | Vtv Therapeutics Llc | Tris(hydroxymethyl)aminomethane salts of a small-molecule glp1r agonist and pharmaceutical compositions and uses thereof. |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SK279958B6 (en) * | 1992-04-02 | 1999-06-11 | Smithkline Beecham Corporation | Compounds exhibiting anti-allergic and anti-inflammatory properties, pharmaceutical composition them containing and their use |
| UY25338A1 (en) * | 1998-01-07 | 2001-08-27 | Smithkline Beecham Corp | METHOD FOR TREATING COPD |
| JP2003534238A (en) * | 1999-12-15 | 2003-11-18 | スミスクライン・ビーチャム・コーポレイション | Salt of cis-4-cyano-4- [3- (cyclopentyloxy) -4-methoxyphenyl] cyclohexane-1-carboxylic acid. |
-
2000
- 2000-05-23 AR ARP000102516A patent/AR024076A1/en not_active Application Discontinuation
- 2000-05-24 KR KR1020017015036A patent/KR20020010669A/en not_active Application Discontinuation
- 2000-05-24 BR BR0010483-3A patent/BR0010483A/en not_active IP Right Cessation
- 2000-05-24 JP JP2000619421A patent/JP2003500356A/en not_active Withdrawn
- 2000-05-24 HU HU0201265A patent/HUP0201265A3/en unknown
- 2000-05-24 TR TR2001/03238T patent/TR200103238T2/en unknown
- 2000-05-24 PL PL00351945A patent/PL351945A1/en not_active Application Discontinuation
- 2000-05-24 CO CO00038192A patent/CO5170527A1/en not_active Application Discontinuation
- 2000-05-24 CN CN00807893A patent/CN1351491A/en active Pending
- 2000-05-24 IL IL14621300A patent/IL146213A0/en unknown
- 2000-05-24 EP EP20000937937 patent/EP1194142A4/en not_active Withdrawn
- 2000-05-24 NZ NZ515169A patent/NZ515169A/en unknown
- 2000-05-24 WO PCT/US2000/014855 patent/WO2000071114A1/en not_active Application Discontinuation
- 2000-05-24 CA CA002375543A patent/CA2375543A1/en not_active Abandoned
- 2000-05-24 CZ CZ20014186A patent/CZ20014186A3/en unknown
- 2000-05-24 MX MXPA01012048A patent/MXPA01012048A/en unknown
- 2000-05-24 AU AU53049/00A patent/AU5304900A/en not_active Abandoned
-
2001
- 2001-11-22 ZA ZA200109624A patent/ZA200109624B/en unknown
- 2001-11-22 NO NO20015699A patent/NO20015699D0/en not_active Application Discontinuation
-
2002
- 2002-09-20 HK HK02106898.8A patent/HK1046630A1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| JP2003500356A (en) | 2003-01-07 |
| NO20015699L (en) | 2001-11-22 |
| CO5170527A1 (en) | 2002-06-27 |
| HK1046630A1 (en) | 2003-01-24 |
| EP1194142A4 (en) | 2002-10-25 |
| KR20020010669A (en) | 2002-02-04 |
| BR0010483A (en) | 2002-02-13 |
| AU5304900A (en) | 2000-12-12 |
| HUP0201265A2 (en) | 2002-08-28 |
| NO20015699D0 (en) | 2001-11-22 |
| IL146213A0 (en) | 2002-07-25 |
| EP1194142A1 (en) | 2002-04-10 |
| WO2000071114A8 (en) | 2001-05-25 |
| TR200103238T2 (en) | 2002-02-21 |
| HUP0201265A3 (en) | 2003-03-28 |
| WO2000071114A1 (en) | 2000-11-30 |
| CZ20014186A3 (en) | 2002-04-17 |
| AR024076A1 (en) | 2002-09-04 |
| PL351945A1 (en) | 2003-07-14 |
| CA2375543A1 (en) | 2000-11-30 |
| MXPA01012048A (en) | 2002-05-06 |
| NZ515169A (en) | 2003-05-30 |
| CN1351491A (en) | 2002-05-29 |
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